In this study, we hypothesized that an intervention against MMP2 activity in vivo would retard the age-associated aortic remodeling and arterial systolic pressure (SBP). Results first show that with advancing age, increased matrix metalloproteinase type II (MMP2) in vascular smooth muscle cells (VSMC) induces activation of ntransforming growth factor-beta1 (TGF-b1); its receptor initiated signaling of SMAD2/3 and increased transcription factor ets-1, which lead to collagen production. Sixteen month (mo) FXBN rats were treated daily with the MMP inhibitor (MMPI), PD166793 (5mg/kg) or placebo for 8 mo. A 16-mo-old untreated group served as an age reference for the 24 mo treated group. As expected, the age-associated increase in MMP activation was substantially inhibited by MMPI (PAGE zymography). Importantly, the twenty-four mo age-associated increases in SBP, intima thickness (IT), media thickness (MT), arterial active TGF-beta1 p-SMAD2/3, and levels of ets-1, fibrilin and collagen were markedly attenuated by MMPI. Notable, the age-associated degeneration of the elastin laminae is also substantially retarded. Furthermore, although levels of a larger molecular fragment of endothelin-1 (ET-1) does not change with age, the smaller more vasoactive fragment of ET-1 ( 14kDa), is dramatically increased. This increase is abolished by long-tern MMPI treatment. Taken together, these results provide proof of concept that age-associated arterial remodeling and the concomitant increase in SBP respond to an intervention to reduce MMP activation, and have potential, substantial clinical importance, given that age-associated arterial remodeling and SBP increases are major risk factors for age-associated arterial diseases.